Paroxysmal noctumal hemoglobinuria (PNH) is an acquired hematologic disorder in which mutations in the PIG-A gene in the hematopoietic stem cell (HSC) leads to deficiency in the production of glycosyl phosphatidylinositol anchored proteins (GPI-AP) in all blood cells. Evidence suggests that PIG-A mutant HSC's have a survival advantage in specific marrow damaging states, and in many patients with PNH, multiple PIG-A mutant HSC's are found. Further, among the HSC's (both PIG-A normal or PIG-A mutant) one PIG-A mutant HSC clone dominates hematopoiesis. The basis of clonal dominance, defined as the capacity of one PIG-A mutant HSC clone to support the majority of hematopoiesis, is unknown and is the focus of our research. We hypothesize that clonal dominance arises from additional genetic or epigenetic alterations separate from the PIG-A mutation. We will approach this research question through comparison and analysis of transcription profiles in T cell clones and HSC's obtained from PNH patients. Candidate genes will be screened through an in vitro assay using transduced mouse HSC's followed by in vivo studies using a murine transplantation model. The University of Utah has an NIH-funded General Clinical Research Center (GCRC), which will be used for evaluation of patients and collection of samples. In addition, the Bioinformatics Core of the GCRC will assist us with analysis of gene expression comparison data generated from the microarray procedure. The principal investigator has assembled a mentor advisory committee, comprised of three outstanding researchers with specific areas of research interest. This group will provide teaching and support across a number of research areas within the field of hematopoiesis. Education of the principal investigator will be supplemented with graduate school courses in molecular biology and biochemistry. The full support of the mentored research award will allow the P.I. to become an independent investigator.